Targeted Natural Interventions
Evening Primrose Oil and Gamma-linolenic acid (GLA)
GLA is an omega-6 fatty acid available from borage oil, evening primrose oil or black currant seed oil. It serves as a precursor for an anti-inflammatory signaling molecule called prostaglandin E1 (Gaby 2006).
In a randomized controlled trial, patients with Raynaud’s phenomenon (with or without scleroderma) were given 6 g of evening primrose oil per day or placebo for 8 weeks. After 6 weeks of treatment, the evening primrose oil group experienced significantly fewer episodes of Raynaud’s phenomenon than those in the placebo group. All of the scleroderma patients noticed improvement; the authors noted this was similar to their previous results using a prostaglandin E1 infusion (Belch 1985). Another study gave scleroderma patients 1 g evening primrose oil three times daily. After one year, patients experienced less pain in their hands and feet, healed ulcers, and improved skin texture (Strong 1985).
Well known for its use in mood modulation, liver disease, and osteoarthritis, SAMe may also be of benefit in scleroderma (Bottiglieri 2002). One study found that intravenous administration of 600 mg SAMe per day for two months, followed by oral ingestion of 400 mg 3 times daily, significantly improved skin quality in patients with systemic sclerosis. After four months, 50% of patients in the study showed a significant improvement in skin texture; one patient even experienced improvement in walking abilities due to increased malleability of skin on the feet and ankles and 4 subjects displayed improved skin fold thickness, another marker of skin texture quality. In 3 patients who underwent skin biopsy, a significant reduction in skin thickness was observed (Oriente 1985).
The antioxidant N-acetylcysteine (NAC) has shown promise in reducing the severity of Raynaud’s phenomenon in people with scleroderma. Several studies have shown that, in patients with Raynaud’s phenomenon as a result of systemic sclerosis, intravenous infusion of NAC effectively increases blood flow to the fingers due to its blood vessel dilating effect; it also reduces the severity and frequency of the episodes of Raynaud’s phenomenon (Salsano 2005; Sambo 2001; Rosato 2009c). NAC has also been shown to reduce lung-related complications of scleroderma (Failli 2002). An open-label trial in which 40 patients were administered intravenous NAC for 5 hours found that vascular function in the kidneys improved following NAC treatment in patients with systemic sclerosis whose disease was not severe (Rosato 2009b). Similarly, systemic sclerosis patients with limited disease severity showed improved markers of liver blood flow following the same intravenous NAC treatment (Rosato 2009a).
Vitamin E has been shown to be useful in the management of a number of autoimmune diseases in which the skin is affected, including scleroderma (Ayres 1978). Various manifestations of scleroderma, including Raynaud’s phenomenon, were reported to respond well to vitamin E; the vitamin E doses to achieve these effects ranged between 200 and 1200 IU per day (Gaby 2006). Moreover, in some cases, vitamin E was also applied topically. For example, one study showed that topical application of vitamin E gel hastened healing of digital ulcers in systemic sclerosis patients (Fiori 2009).
In a clinical trial, vitamins C and E were combined with cyclophosphamide and compared to cyclophosphamide alone in patients with systemic sclerosis. The combination of the two antioxidant nutrients and cyclophosphamide led to less progressive skin thickening and a trend toward improved lung function compared to treatment with only cyclophosphamide (Ostojic 2011). A 24-week trial found that coadministration of the anti-inflammatory and vasodilating drug pentoxifylline with vitamin E reduced skin fibrosis in patients with systemic sclerosis (de Souza 2009).
Several studies have shown that green tea, and one of its main active constituents, epigallocatechin gallate (EGCG), has beneficial effects on the endothelium – the delicate inner lining of blood vessels, which is compromised in scleroderma (Shenouda 2007; Widlansky 2007; Alexopoulos 2008). Evidence also suggests that EGCG can suppress tissue fibrosis by inhibiting a signaling pathway that promotes excessive accumulation of collagen (Park 2008).
Experimental studies are strongly suggestive of the therapeutic potential of green tea EGCG in treating autoimmune diseases (Wu 2011). In addition, a laboratory study found that EGCG decreased collagen secretion by fibroblasts. The authors concluded that their results “suggest that the antioxidant, EGCG, can reduce ECM [extracellular matrix] production, the fibrotic marker CTGF [connective tissue growth factor] and inhibit contraction of dermal fibroblasts from SSc [systemic sclerosis] patients” (Dooley 2010). Numerous other studies have noted multiple antifibrotic actions of green tea constituents (Xiao 2013; Chang 2013; Tsai 2013; Cai 2013). While there is a need for future human clinical trials to confirm this, bearing in mind the well-documented cardiovascular effects of green tea and EGCG in humans, patients with scleroderma and other autoimmune diseases may benefit from supplementing with green tea EGCG (Wu 2011).
4-Aminobenzoic acid (PABA)
Sometimes referred to as a member of the B-vitamin family, PABA is a water-soluble organic compound that has been studied as far back as the 1940s as a remedy for scleroderma (Zarafonetis 1948). Case reports of the effects of PABA in scleroderma patients are dispersed throughout the scientific literature over the decades leading up to the 1980s, at which point more rigorous analyses were published (Meyers 1977; BMJ 1968; Gougerot 1951). Evidence from retrospective studies indicate PABA is associated with several benefits for scleroderma patients, including improved survival, skin softening, and better maintenance of lung function over time (Zarafonetis 1988a,b; Zarafonetis 1989). Unfortunately, in 1994, a double-blind, placebo-controlled trial failed to show that PABA was superior to placebo for treating skin manifestations of scleroderma (Clegg 1994). Despite the results of this study, case reports of benefits in skin conditions related to scleroderma continue to be published (Gruson 2005). Although the mechanism(s) by which PABA may modify scleroderma are unclear, one study showed that the compound was able to inhibit growth of fibroblasts derived from scleroderma patients (Priestley 1979). Additional studies are needed to evaluate PABA as a treatment for scleroderma.
Melatonin, also known as the "sleep hormone," is produced and secreted by the pineal gland during nighttime (Pandi-Perumal 2006). Melatonin is involved in sleep regulation, as well as in a number of other cyclical bodily activities.
Melatonin has several beneficial effects on the endothelium that are directly relevant for scleroderma: it scavenges free radicals, activates antioxidant defense enzymes, reduces blood pressure, and increases nitric oxide bioavailability (Scheer 2004; Rodella 2013). Its ability to protect against endothelial damage, blood vessel constriction, platelet aggregation, and the accumulation of excessive amounts of white blood cells in tissues (leukocyte infiltration) might explain the beneficial effects of supplementation that were described in patients with scleroderma (Rodella 2013). In a study that included 5 patients, supplementation of melatonin in combination with vitamin E and ACTH, a hormone secreted by the anterior pituitary gland and important for the health of the neuroimmunoendocrine system, achieved a partial response in all patients after one month of treatment, and disease progression was stopped in all five patients when the treatment was continued further (Todisco 2006). A laboratory study investigated the effect of melatonin on human skin fibroblasts (connective tissue cells), and reported that it caused an over 80% inhibition of the growth and multiplication of fibroblasts derived from the skin of healthy individuals and scleroderma patients (Carossino 1996).
Gotu kola (Centella asiatica)
Gotu kola (Centella asiatica) is an herb found in most tropical and subtropical countries, including India, South Africa, Madagascar, and Eastern Europe (Gohil 2010). Gotu kola alleviates microcirculatory problems and may help inflammatory skin conditions, such as lupus, varicose ulcers, eczema, atopic dermatitis, and psoriasis (Belcaro 2011; Gohil 2010). In addition to being an anti-inflammatory, gotu kola is also an antioxidant that can help control oxidative stress associated with inflammation and/or infections (Belcaro 2011; Gohil 2010). It also aids wound healing and is used for scar management (Maquart 1999; Bonte 1994; Widgerow 2000; Paocharoen 2010; Belcaro 2011).
Gotu kola has been used for localized and systemic scleroderma with positive results. After 6 months of supplementation in oral form with 30 mg/day (10 mg, three times a day), a study on 12 patients with systemic sclerosis showed a decrease of vascular disorders, hard lesions, hyperpigmentation, and improvement in the patients’ general condition. A beneficial response was also obtained with local application of gotu kola ointment on finger ulcers, and the therapy was well tolerated (Guseva 1998).
Curcumin is a major component of the spice turmeric. Turmeric has been used in Ayurvedic medicine to treat a wide range of conditions, and practitioners of alternative medicine often recommend curcumin as a treatment for inflammatory and autoimmune diseases (Aggarwal 2009,2011; Jurenka 2009). Moreover, curcumin has been shown in the last two decades to have potent immunomodulatory, neuroprotective, and anti-cancer effects (Jagetia 2007; Zhou 2011; Sharma 2005; Cole 2007; Jurenka 2009). Because scleroderma is a disease that involves exaggerated collagen deposition and excessive growth (proliferation) of fibroblasts, curcumin may be able to provide a therapeutic benefit through its ability to suppress the proliferation of fibroblasts (Tourkina 2004; Punithavathi 2003; Smith 2010). Laboratory studies reveal that curcumin suppresses transforming growth factor beta (TGF-β), a profibrotic signaling molecule implicated in the development of scleroderma (Song 2011). Another study found that curcumin caused cell death (apoptosis) in scleroderma lung fibroblasts but not in normal lung fibroblasts. The authors concluded “these observations suggest that curcumin may have therapeutic value in treating scleroderma…” (Tourkina 2004).
Vitamin D is a precursor to the hormone calcitriol, which exerts a vast array of actions throughout the body. Calcitriol plays an especially prominent role in modulation of the immune system (Panichi 2003). Moreover, associations have been made between low blood levels of vitamin D and autoimmune and inflammatory disorders, including scleroderma (Agmon-Levin 2012; Vacca 2011).
In one study, scleroderma patients were more likely to be deficient in vitamin D compared to healthy control subjects. In addition, scleroderma patients with higher vitamin D levels had less extensive skin involvement than those with low levels. Higher vitamin D concentrations were associated with less skin fibrosis as well (Arnson 2011). These findings are in line with experimental evidence that suggests calcitriol and related vitamin D metabolites can modulate growth factor signaling, thereby reducing the propensity of fibroblasts to promote fibrosis (Slominski 2013).
Other clinical trials and case reports have shown that direct administration of calcitriol results in symptomatic improvement in scleroderma patients. In one small trial conducted on three patients with localized scleroderma, calcitriol administration for 7 months improved skin tightness and joint mobility (Hulshof 1994). Another trial showed oral calcitriol treatment considerably improved skin lesions in 5 of 7 children with scleroderma (Elst 1999). Similarly, in a trial conducted on 11 scleroderma patients, calcitriol treatment for up to 3 years was associated with significant improvements compared to baseline (Humbert 1993).
These findings give credence to the notion that maintenance of adequate vitamin D blood levels should be a priority for scleroderma patients. Life Extension suggests that most adults target an optimal 25-hydroxyvitamin D level of 50 – 80 ng/mL.